Lung is not only a respiratory organ, but also a metabolic organ. Pulmonary vascular beds are extremely wide and this helps the lung to metabolite various vasoactive substances and to perform the gas exchange. Lungs can metabolite or inactivate PGE₂, PGF_2α, LTC₄, LTD₄, LTE₄, serotonin, acetylcholine, bradykin, histamine and norepinephrine, and can produce histamine, serotonin, PAF, LTs, thromboxane A₂ and various PGs. Percentage inactivation of PGs and LTs are closely dependent to the width of pulmonary vascular beds. The percentage inactivation showed a marked decrease by increasing the dose of administered vasoactive substances, and also showed a marked decrease by clumping the left pulmonary artery trunk or by infusing glass beads (100μ of diameter) into the pulmonary artery.
Chemical mediators, histamine and SRS-A can interact and regulate the release of other chemical mediator, and PAF accelerates the release of histamine, SRS-A, LTC₄ from passively sensitized guinea pig lung tissue following the antigen challenge.
It is well known that cigarette smoking has diverse effects not only on the airway system but also on the pulmonary and systemic circulation.

View full abstract

To understand the physiological significance of erythrocyte membrane aspartic proteinase (EMAP), its catalytic properties and possible mechanisms for its activation were investigated, and the results are as follows. (1) The enzyme was indistinguishable from cathepsin E but not cathepsin D enzymatically and immunochemically. (2) The enzyme was found at high levels in neutrophils, lymphocytes and platelets as well as erythrocytes. (3) The membrane-bound latent enzyme was activated by various procedures that induce the disturbance of normal erythrocyte membrane organization, e.g., by treatments with phospholipase C and trypsin or simply by heating at 40°C. The activation was accompanied by dissociation of the enzyme from the membrane. (4) When the young erythrocyte obtained by density gradient centrifugation on Percoll gradients were aged in vitro, a decrease in the membrane-bound form of EMAP and an increase in the soluble form were observed in a time-dependent manner. The erythrocyte aging also caused an increase in the membrane-bound form of cytosolic proteins such as hemoglobin.

View full abstract

We previously reported that mouse macrophages became easily permeable to phosphoric esters and nucleotides by the in vitro treatment with external ATP. To study in vivo effects of ATP, the functional properties of peritoneal macrophages in intraperitoneal ATP-injected mouse were investigated. The macrophages at 5 hr after the ATP injection exerted low activity of ecto-5'-nucleotidase, suggesting exudate macrophages not resident macrophages. At 18 hr and 4 days, the peritoneal macrophages also showed low activities of the enzyme. Moreover, those macrophages had high oxygen radical formations and inhibited cytostatically growth of Salmonella bacteria. In contrast, thioglycollate, proteose·peptone and LPS are well known to induce peritoneal exudate macrophages, and also showed high oxygen radical formations and antimicrobial activities as similar as one of ATP. These stimulatives, however, did not induce the permeability change of macrophages in vitro. By the administration of macrophages which were experienced in the permeability change in vitro with ATP treatment, the similar macrophages as those obtained from the in vivo ATP direct injection appeared in the peritoneal exudate cells. From these results, it is possible to speculate that the permeability change of macrophages and then the induction of exudate macrophages occur in vivo, when a large quantity of external ATP would be locally present.

View full abstract

After the treatment of thermal injury, contents of leukotriene C₄ (LTC₄) increased significantly at early stage and then kept the high level of LTC₄ during the inflammation. Administration of vitamin A (VA) on vitamin A deficient- (AD) rats suppressed LTC₄ induction in the lung and also inflammation and then gradually induced the significant decrease of LTC₄ contents to the normal level 3 days after treatment of thermal injury. Synthesis of 6KPGF_1α in the lung of AD rat was induced gradually until 24 hours after thermal injury. While the administration of VA to AD-rat enabled in the lung to induce the synthesis of 6-KPGF_1α enough at early stage of thermal injury. After this induction, the production of 6KPGF_1α gradually decreased. These results suggest that VA will suppress specifically the induction of lipoxygenase products but will not interfere the synthesis of cyclooxygenase products.

View full abstract

The initial aim of the present study was to clarify the role of platelet-activating factor (PAF-acether) : acetylhydrolase in the catabolism of PAF-acether in cultured human vascular endothelial (HVE) cells stimulated by thrombin. When HVE cells were pretreated with 2mM phenylmethylsulfonyl fluoride (PMSF, a serine proteinase inhibitor), about 2 times more PAF-acether was produced in response to 2.5 U/ml thrombin stimulation. The enhancing effect of PMSF on the mediator production could be partially explained by the inhibition of PAF-acether degradation in HVE cells, since the acetylhydrolase activity was suppressed by 32.7% in PMSF-treated cells, However, the activity of lyso PAF-acether: acetyl CoA acetyltransferase in unstimulated or thrombin-stimulated cells was 11.0-26.9% higher in PMSF-treated cells, although thrombin caused similar activation of the enzyme (3.4-4.1 fold) in both control and PMSF-treated cells. Furthermore, PMSF pretreatment increased the content of lyso PAF-acether and thrombin-induced radioactivity release from HVE cells loaded wth [³H] arachidonic acid, suggesting a higher activity of phospholipase A₂ in PMSF-treated cells. These results suggest that the enhancement of thrombin-induced PAF-acether formation in PMSF-treated HVE cells is not only due to the inhibition of the acetylhydrolase, but also due to the influences on the activities of the acetyltransferase and other enzymes such as phospholipase A₂.

View full abstract

It is well known that neutrophils are involved in the inflammatory process. Although neutrophils are the most important factor in preventing bacterial infection, the adverse effects of neutrophils on the cellular function are also recognized. We recently revealed that a highly toxic substance, 9, 10-epoxy-12-octadecenoate, is biosynthesized by human neutrophils, thus it was named leukotoxin. This study was designed to investigate whether or not leukotoxin is involved in the genesis of pulmonary oxygen toxicity and adult respiratory distress syndrome (ARDS) . Experimental study: After exposure to hyperoxia for 60 h, rats showed acute pulmonary edema, which was evidenced by increased lung weight, albumin concentrations, and angiotensin-converting enzyme (ACE) activities in lung lavages. Neutrophil recruitment in lung lavages was observed. Leukotoxin was also detected in lung lavages of rats after exposure to hyperoxia for 60 h. Intravenous injection of leukotoxin (100μmol/kg) caused acute edematous lung injury. Clinical study: In the lung lavages obtained from 5 patients with ARDS, significant increases in albumin concentrations and ACE activities were observed compared with those from subjects without pulmonary diseases. Moreover, considerable amounts of leukotoxin were observed in lung lavages from patients with ARDS.
Hence, these results indicate that leukotoxin biosynthesized by neutrophlis might be closely related to the genesis of pulmonary oxygen toxicity and lung injury observed in patients with ARDS.

View full abstract

This study was performed to make a better lipid microsphere (LM) preparation of PGE₁ derivatives. At first, we measured the inhibitory effects on human platelet aggregation by PGE₁ and its several esters. Subsequently, we measured their activity after incubation in human serum. The results showed that the activity of PGE₁ butyl ester, methyl ester or pivaryl ester became stronger after the incubation in serum. After intravenious injection, PGE₁ butyl ester, methyl ester or pivaryl ester may be changed to PGE₁ by plasma esterase. When the LM prepations of PGE₁ and its several esters were incubated in 1.6% bovine serum albumin solution, it was shown that PGE₁ as such was released rapidly from LM, while the release of PGE₁ butyl ester, PGE₁ methyl ester and PGE₁ pivaryl ester were slow.
Thus PGE₁ butyl ester, methyl ester, pivaryl ester in LM, injected intravenously, may not be released largely in plasma before the distribution of LM to the target site. These data suggest that LM preparation of PGE₁ butyl ester, methyl ester or pivaryl ester would be a better LM preparation than lipo-PGE₁.

View full abstract

The leukotrienes are derived from arachidonic acid via a lipoxigenase pathway and are potent mediators of inflammation and allergy. Leukotriene B4 (LTB4) not only causes chemotaxis, chemokinesis and degranulation of polymorphonuclear leukocytes but also involves in the enhanced production of interleukin 1 from macrophages, interleukin 2 and interferon-gamma production from T lymphocytes and activation of natural killer (NK) cells. Leukotriene C4 (LTC4) enhances vascular permeability and induces tissue edema. Recently, it is suggested that leukotrienes may be key mediators in inflammatory liver diseases. In this study, to clarify the relation of leukotrienes to liver injury, we have examined the blood levels of LTB4 and LTC4 in chronic hepatitis.
Leukotrienes were assayed using with the combination of technique of reverse-phase high-performance liquid chromatography and radioimmunoassay.
The following results were obtained. (a) The blood level of LTB4 in chronic hepatitis was significantly higher than control group. (b) No significant difference of blood level of LTC4 between chronic hepatitis and control group was obtained.
These results suggested that increased levels of LTB4 may be involved in the inflammatory and immunologic events in liver tissue in chronic hepatitis.

View full abstract

In this study biopsy specimens of erythema nodosum-like lesions from 18 patients with Behçet's disease were examined with the electron microscope to elucidate the close relationship between lymphocytes and/or macrophages and fibroblasts in the perivascular regions of the corium accompanied by marked edematous changes. Adhesion of lymphocytes and/or macrophages to fibroblasts were observed in 11 of the 18 patients in whom biopsy specimens were collected one to four days after the onset of the skin lesions. The lymphocytes adhering to fibroblasts contained a number of polyribosomes and few organelles in the cytoplasm. The fibroblasts with these lymphocytes showed remarkable development of rough endoplasmic reticulum and any other cytoplasmic organelles, indicating activated cellular function as collagen synthesis. In the triads of lymphocyte-fibroblast-macrophage as well as adhesion of macrophages to fibroblasts, morphological profiles of the fibroblasts suggested strongly suppression of collagen synthesis. Our findings indicate that fibroblasts are regulated directly by adhesion of lymphocytes and/or macrophages in fibrous repair of the erythema nodosumlike lesions of Behçet's disease.

View full abstract

Plasma exchange therapy to the immune complexs of patients with rheumatoid arthritis is now extensively applied. However, remission duration is variable in each cases, shorter or longer. In view of this, we tried to treat with plasma exchange (double membrane filtration) and administration of lobenzarit disodium. This combination therapy have produced remarkable clinical improvement and immune complex have been decreasing for more than 12 months.

View full abstract

Density analysis and ultrastructural observation were performed on eosinophils from patients with atopic dermatitis (AD) . Before treatment, density analysis displayed lower peak density and greater number of hypodense eosinophils compared with normal subjects. After treatment with ketotifen, profiles demonstrated similar peak density to normal subjects following decreased number of hypodense eosinophils which was directly proportional to remission of clinical symptoms. Hypodense eosinophils were morphologically characterized by partial or complete degranulation. It is suggested that hypodense eosinophils may contribute clinical manifestation of AD and that ketotifen may give clinical remission for patients with AD by decreasing such cells.

View full abstract